The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge
The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge
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DOI：
10.1038/sj.onc.1210016
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发表时间：
2007-04-05
期刊：
影响因子：
8
通讯作者：
Humbert, P. O.
中科院分区：
文献类型：
--
作者：
Dow, L. E.;Kauffman, J. S.;Humbert, P. O.
人类Scribble的表达改变与浸润性上皮癌相关，然而，其在肿瘤发展中的作用仍不清楚。果蝇Scribble中的突变导致上皮细胞的极性丧失、过度增殖和3D肿瘤性过度生长。利用果蝇中的互补研究，我们最近证明了人类Scribble的表达也可以调节极性和限制组织过度生长。在这里，我们已经进行了详细的研究人类涂鸦功能的极化乳腺细胞系，MCF 10A。我们发现，虽然Scribble似乎并不需要在MCF 10A细胞的顶部-基底极性或增殖控制，Scribble是必不可少的极性控制与定向上皮细胞迁移。Scribble-depleted MCF 10A细胞在体外伤口闭合和趋化运动中表现出缺陷。在伤口边缘的细胞不能粘附，显示减少的片状伪足形成和受损的Cdc 42和Rac 1的募集到前缘。此外，我们表明，这种功能是相关的，在体内的Scribble突变小鼠表现出缺陷的表皮伤口愈合。该数据确定了哺乳动物Scribble在调节定向上皮迁移中特别涉及的极性中的重要作用。
Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.